3-Oximino-17{60 -propadienyl-substituted-4,9-gonadienes

ABSTRACT

The compounds are 3-oximino-17 Alpha -propadienyl-substituted steroids, e.g., 17 Alpha -propadlenylestra-4,9-dien-17 Beta -ol3-one oxime, and are useful in the regulation of reproduction in warm-blooded animals.

United States Patent v .1191

Bacso et al.

[ 51 Sept. 23, 1975 3-OXlMINO-l7a-PROPADIENYL- SUBSTITUTED-4,9-GONADIENES Inventors: lmre Bacso, Morristown, N.J.;

Eugene E. Galantay, Liestal, Switzerland Assignee: Sandoz Inc., East Hanover, NJ.

Filedf Sept. 19, 1973 Appl. No.: 398,566

Related U.S. Application Data Continuation-impart of Ser. No. 154,190, June 17, 1971, abandoned.

U.S. C1. 260/397.5; 260/397.4; 424/238 Int. C1. C07J 7/00 Field of Search/Machine Searched Steroids;

Primary Examiner-Elbert L. Roberts Attorney, Agent, or FirmGerald D. Sharkin; Richard E. Vila; Frederick H, Weinfeldt [57] ABSTRACT The compounds are 3-oximino-17a-propadienylsubstituted steroids, e.g., l7a-pr0pad1enylestra-4,9- dien-l7B-o1-3-one oxime, and are useful in the regulation of reproduction in warm-blooded animals.

5 Claims, No Drawings 1 3-OXIMINO-17a-PROPADIENYL-SUBSTITUTED- 4,9-GONADIENES This is a continuation-in-part of copending application Ser. No. 154,190 (filed June 17, 1971), now aban- .doned.

This invention relates to steroidal compounds, and more particularly to 3-oximino-l7a-propadienylsubstituted-4,9-gonadienes and to the preparation of such compounds as well as to therapeutic compositions which contain such compounds and the use of such compounds.

The compounds of this invention, i.e., Compounds I, are conveniently represented by the formula:

RON

wherein R is defined above, by conventional means for preparing an oxime derivative from a 3-keto-steroid (Process a). For example, by treatment of a suitable 3- keto steroid (11) with a suitable hydroxylamine reagent, to yield the oxime, i.e., a Compound 1 wherein R is a hydrogen atom, and further treatment thereof where a compound 1 is desired wherein R is alkanoyl, with an alkanoylating agent (Process 12).

3-Keto-steroids suitable as starting materials (compounds II) for the preparation of compounds I are described in the literature, e.g. in Belgian Pat. Nos. 742,137 and 766,147 and US. Pat. Nos. 3,661,940 and 3,719,670.

A convenient method for carrying out Process (a) to obtain a Compound I wherein R is a hydrogen atom, involves treating a Compound 11, under anhydrous conditions, with a hydroxylamine reagent, preferably hydroxylamine acetate in an inert organic solvent, e.g. a lower alkanol, such as methanol or ethanol, at moderate temperatures, eg conveniently at room temperature, or at other temperatures preferably lower than the reflux temperature of the solvent. The hydroxylamine reagent may be prepared separately or in situ, e.g. from a hydroxylamine salt, e.g. the hydrochloride, and a base such as sodium acetate, sodium hydroxide or pyridine. Where pyridine is employed as base, it may serve in excess as solvent for the reaction.

A convenient method of carrying out Process (12) to obtain a Compound I wherein R is lower alkanoyl, involves treating a Compound I wherein R is a hydrogen atom, with an alkanoylating agent. It is preferred that in Process (17) alkanoylating agents which are not strongly acidic be employed, as the l7a-propadienylsubstituent may be adversely affected by such conditions. A lower aliphatic acid or acid anhydride may be used as the alkanoylating agent in the presence of an acid binding agent, e.g. acetic acid anhydride with pyridine. The alkanoylation reaction may be carried in an inert organic solvent, e.g. benzene, at moderate temperatures, e.g. -l0 to 50C., preferably at room temperature. Where the alkanoylating agent is suitable as a solvent, it may be used in excess to serve as solvent.

The Compounds I prepared as described above may be recovered and refined by means conventional in the art, e.g. by recrystallization or column or layer chromatography.

The compounds of formula (I) are useful because they possess pharmacological properties in animals. In particular, such compounds exhibit progestational ac tivity and are therefore useful in the control of fertility in female warm-blooded animals and regulation of estrus or the menstrual function thereof, and in addition are also useful as luteolytic agents in the prevention or interruption of pregnancy in such animals. The progestational activity is indicated by the wellknown Clauberg test; the method basically described in Endocrinology 63 (1958) 464 wherein a rabbit is given 0.001 mg. to 1.0 mg. of active agent. Luteolytic activity is indicated by selecting female estrous white rats from a colony, treating them with the test compound for 4 days and then caging them with fertile males; beginning on the following day, the females are treated for an additional 10 days with the compound being tested; and on the third day following the last treatment the females are sacrificed and the uteri checked for implantation sites (the absence or regression of which being taken as a positive result). Luteolytic activity may also be indicated by a rabbit pseudopregnancy test in which adult New Zealand White female rabbits are injected intravenously with international units of Human Chorionic Gonadotrophin (HCG) to induce ovulation and formation of corpora lutea (pseudopregnancy. The day of treatment with HCG is considered day-1 of pseudopregnancy. lmmediately prior to the l-ICG treatment a 2 ml. blood sample (via heart puncture) is collected. Two ml. blood samples are obtained on various days through dayl 2 of pseudopregnancy. On day-3 of pseudopregnancy, groups of females are treated orally or injected subcutaneously with corn oil (controls) or the test compound in corn oil. Treatments are continued through day-8 of pseudopregnancy. Blood samples are analyzed for progestin content according to the method of Johansson et a1. (Endocrinology Vol. 82, 143-148, 1968). A compound is judged to be luteolytic if plasma progestin levels have returned to pretreatment levels by dayl 2 of pseudopregnancy. Luteolytic activity may be further demonstrated in the Rhesus monkey by a test in which treatments with the test compound are initiated 4 days following the estrogen surge and continued daily for a total of six treatments (last treatment on day-9 following the estrogen surge). Blood levels of progestins are monitored daily by the abovementioned method of Johansson et al. A compound is judged to be active if blood levels of progestins are returned to base line levels and maintained at these levels as compared to control females. Positive results demonstrate a luteolytic activity of the compound in a menstrual cycling species.

These compounds may be combined with a pharmaceutically acceptable carrier or adjuvant in a manner which is conventional in the pharmaceutical art. They may be administered orally or parenterally. The dosage will vary depending upon the mode of administration utilized and the particular compound employed. However, in general, satisfactory results are obtained in female warm-blooded animals, e.g. mammals, when the compounds are administered at a daily dosage of from about 0.005 mg. to 30 mg., e.g. about 0.015 mg. to mg. to control fertility or regulate estrus or the menstrual function; and for the prevention or interruption of pregnancy by luteolytic activity at a daily dosage of from about 1 mg. to' 100 mg., e.g. from about 1 mg. to 20 mg. daily for from about 1 to 6 days during the luteal phase. Convenient dosage forms suitable for internal administration comprise from about 0.005 mg. to 100 mg., e.g. from0.0l5 mg. to 20 mg. of the compound in admixture with a solid or liquid pharmaceutical carrier or diluent.

The compounds I of this invention contrast with the known compound l7a-propadienylestra-4,9-dienl7Bol-3-one which has a different spectrum of activity, e.g. it has significant estrogenic activity.

A representative formulation suitable for oral administration is a capsule (250 mg.) prepared by standard techniques which contains the following:

Ingredient Weight (mg) l7a propadienylestra-4,9-dienl 7B-ol-3-one 5 I oxime I Inert solid diluent (starch, lactose, kaolin) 245 In the following examples, illustrating the invention, all temperatures are C. and room temperature is 20 to 30C., unless indicated otherwise.

EXAMPLE 1 l7a-Propadienylestra-4,9-dien-17,8-01-3-one oxime water and the solids which have separated are collected 4 dien- 17,8-01-3-one oxime, or l 7oi-propndienyl- 1 3m. propylgona-4,9-dien- 1 7,8-01-3-one oxime.

EXAMPLE 2 N-Acetoxy-17a-propadienylestra-4,9-dien- 1 7/3-01- 3-one oxime EXAMPLE 3 7 Tablets and Capsules Suitable for Oral Administration Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in the control of fertility in mammals:

Weight (mg.)

Ingredient Tablet Capsule l 7a-Propadienylestra-4,9-dien-17B- ol-3-one oxime 0.5 0.5 tragacanth l0 lactose 247 299.5 corn starch 25 talcum 15 magnesium stearate 2.5

Total 300 mg. 300 mg.

EXAMPLES 4 AND 5 Sterile Suspension for Injection and Oral Liquid Suspension Weight (mg) erile Oral Ingredients Injectable Liquid Su- Suspension spension l7a-Propadienylestra-4,9-dien- 0.2 0.5 l7B-o1-3-one oxime Sodium carboxy methyl cellulose 1.25 12.5 U.S.P. Y

Methyl cellulose 0.4 Polyvinylpyrrolidone 5 Lecithin 3 Benzyl alcohol 0.01 Magnesium aluminum silicate 47.5 Flavor q.s. Color q.s. Methyl paraben, U.S.P. 4.5 Propyl paraben, U.S.P. w 1.0 Polysorbate (e.g. Tween 80) 5 Continued Weight (mg) Sterile Oral Ingredients I lnjeclable Liquid Su- Suspension spension U.S.P. RON Sorbitol solution, 70%, U.S.P. 2,500 Buffer agent to adjust pH for wh i d'dtb'l't S a y f ifljicfion' i R !S a hydrogen atom or alkanoyl having from two to m 1 5 ml four carbon atoms;

R is unbranched alkyl having from one to three car- "q.s. =quantity sufficient. bon atoms 2. A compound of claim 1 wherein R is a hydrogen atom.

3. The compound of claim 2 wherein R is methyl. What is claimed is: l 4. A compound of claim 1 wherein R is alkanoyl. l. A compound of the formula: 5. A compound of claim 1 in which R is methyl. 

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 wherein R is a hydrogen atom.
 3. The compound of claim 2 wherein R1 is methyl.
 4. A compound of claim 1 wherein R is alkanoyl.
 5. A compound of claim 1 in which R1 is methyl. 